Otoferlin Is Required for Proper Synapse Maturation and for Maintenance of Inner and Outer Hair Cells in Mouse Models for DFNB9

Frontiers in Cellular Neuroscience

Albert Justin Franke¹  Ursula Stalmann¹  Nicola Strenzke¹  Ellen Reisinger²  Hanan Al-Moyed³ 

[1] Auditory Systems Physiology Group, Department of Otolaryngology and Institute for Auditory Neuroscience, SFB 889 project A06, University Medical Center Göttingen, Göttingen, Germany;Gene Therapy for Hearing Impairment Group, Department of Otolaryngology, Head and Neck Surgery, University of Tübingen Medical Center, Tübingen, Germany;Molecular Biology of Cochlear Neurotransmission Group, Department of Otolaryngology, University Medical Center Göttingen, Göttingen, Germany;

关键词: inner hair cells;    outer hair cells;    synapse maturation;    degeneration;    otoacoustic emissions;    hearing loss;   

DOI  :  10.3389/fncel.2021.677543

来源: DOAJ

【 摘 要 】

Deficiency of otoferlin causes profound prelingual deafness in humans and animal models. Here, we closely analyzed developmental deficits and degenerative mechanisms in Otof knock-out (Otof–/–) mice over the course of 48 weeks. We found otoferlin to be required for proper synapse development in the immature rodent cochlea: In absence of otoferlin, synaptic pruning was delayed, and postsynaptic boutons appeared enlarged at 2 weeks of age. At postnatal day 14 (P14), we found on average ∼15 synapses per inner hair cell (IHC) in Otof–/– cochleae as well as in wild-type controls. Further on, the number of synapses in Otof–/– IHCs was reduced to ∼7 at 8 weeks of age and to ∼6 at 48 weeks of age. In the same period, the number of spiral ganglion neurons (SGNs) declined in Otof–/– animals. Importantly, we found an age-progressive loss of IHCs to an overall number of 75% of wildtype IHCs. The IHC loss more prominently but not exclusively affected the basal aspects of the cochlea. For outer hair cells (OHCs), we observed slightly accelerated age-dependent degeneration from base to apex. This was associated with a progressive decay in DPOAE amplitudes for high frequency stimuli, which could first be observed at the age of 24 weeks in Otof–/– mice. Our data will help to plan and predict the outcome of a gene therapy applied at various ages of DFNB9 patients.

【 授权许可】

Unknown